4.1. Therapeutic indications

Juluca is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least six months with no history of virological failure and no known or suspected resistance to any non-nucleoside reverse transcriptase inhibitor or integrase inhibitor (see section 5.1).

4.2. Posology and method of administration

Juluca should be prescribed by physicians experienced in the management of HIV infection.

Posology

The recommended dose of Juluca is one tablet once daily. Juluca must be taken with a meal (see section 5.2).

Separate preparations of dolutegravir or rilpivirine are available in cases where discontinuation or dose adjustment of one of the active substances is indicated (see section 4.5). In these cases, the physician should refer to the Summary of Product Characteristics for these medicinal products.

Missed doses

If the patient misses a dose of Juluca, the patient should take Juluca with a meal as soon as possible, providing the next dose is not due within 12 hours. If the next dose is due within 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

If a patient vomits within 4 hours of taking Juluca, another Juluca tablet should be taken with a meal. If a patient vomits more than 4 hours after taking Juluca, the patient does not need to take another dose of Juluca until the next regularly scheduled dose.

Elderly

There are limited data available on the use of Juluca in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2).

Renal impairment

No dosage adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease, the combination of Juluca with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population (see section 5.2).

Hepatic impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). Juluca should be used with caution in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh score C); therefore, Juluca is not recommended in these patients (see section 5.2).

Paediatric population

The safety and efficacy of Juluca in children and adolescents aged less than 18 years have not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Pregnancy

The safety and efficacy of Juluca in pregnancy have not yet been established. Limited data are available regarding the use of dolutegravir during pregnancy. Lower exposures of dolutegravir and rilpivirine were observed during pregnancy. No recommendations for dose adjustments can be made for Juluca. Therefore, use of Juluca during pregnancy is not recommended (see sections 4.4, 4.6, 5.1 and 5.2).

Method of administration

Oral use

Juluca must be taken orally, once daily with a meal (see section 5.2). It is recommended that the film-coated tablet be swallowed whole with water and not be chewed or crushed.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Co-administration with the following medicinal products:

- fampridine (also known as dalfampridine);

- carbamazepine, oxcarbazepine, phenobarbital, phenytoin;

- rifampicin, rifapentine;

- proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole;

- systemic dexamethasone, except as a single dose treatment;

- St John's wort (Hypericum perforatum).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Juluca should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with Juluca after the onset of hypersensitivity may result in a life-threatening allergic reaction.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids and weight, there is in some cases evidence for a treatment effect. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Cardiovascular

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 5.1). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Juluca should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.

Opportunistic infections

Patients should be advised that Juluca does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Patients with hepatitis B or C

No clinical data are available in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus. Limited data is available in patients with hepatitis C co-infection. A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected. Monitoring of liver function is recommended in patients with hepatitis B and/or C co-infection.

Interactions with other medicinal products

Juluca should not be administered with other antiretroviral medicinal products for the treatment of HIV (see section 4.5).

Juluca should not be co-administered at the same time as H2-receptor antagonists. These medicinal products are recommended to be administered 12 hours before or 4 hours after Juluca (see section 4.5).

Juluca should not be co-administered at the same time as antacids. These medicinal products are recommended to be administered 6 hours before or 4 hours after Juluca (see section 4.5).

Calcium or iron supplements, or multivitamins should be co-administered at the same time as Juluca, with a meal. If calcium or iron supplements, or multivitamins cannot be taken at the same time as Juluca, these supplements are recommended to be administered 6 hours before or 4 hours after taking Juluca (see section 4.5).

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping co-administration of Juluca with metformin, to maintain glycaemic control (see section 4.5). Metformin is eliminated renally and therefore, it is of importance to monitor renal function when co-treated with Juluca. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45– 59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.

Juluca should not be taken with any other medicinal product containing dolutegravir or rilpivirine, except in case of co-administration with rifabutin (see section 4.5).

Pregnancy

The safety and efficacy of Juluca in pregnancy have not yet been established. Limited data are available regarding the use of dolutegravir during pregnancy. Lower exposures of dolutegravir or rilpivirine were observed when taken once daily, in combination with a background regimen, during pregnancy. In phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure. No recommendations for dose adjustments can be made for Juluca. Therefore, use of Juluca during pregnancy is not recommended (see sections 4.6, 5.1 and 5.2).

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are Cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Excipients

Juluca contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Juluca is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. Juluca contains dolutegravir and rilpivirine, therefore, any interactions identified with these active substances are relevant to Juluca. Interaction studies have only been performed in adults.

Effect of other medicinal products on the pharmacokinetics of dolutegravir and rilpivirine

Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT)1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, cytochrome P450 (CYP)3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP); therefore, medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). Co-administration of Juluca and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 1).

The absorption of dolutegravir is reduced by certain anti-acid medicinal products (see Table 1).

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of Juluca with medicinal products that induce CYP3A may result in decreased plasma concentrations of rilpivirine, which could reduce the therapeutic effect of Juluca (see Table 1). Co-administration of Juluca with medicinal products that inhibit CYP3A may result in increased plasma concentrations of rilpivirine (see Table 1).

Co-administration of Juluca with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of Juluca.

Effect of dolutegravir and rilpivirine on the pharmacokinetics of other medicinal products

Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1). In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 1 and sections 4.3 and 4.4).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT)1 and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.

Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

Rilpivirine inhibits P-gp in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicinal products transported by P-gp that are more sensitive to intestinal P-gp inhibition, e.g. dabigatran etexilate.

Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown.

Interaction table

Selected established and theoretical interactions between dolutegravir, rilpivirine and co-administered medicinal products are listed in Table 1.

(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, minimum observed concentration as “Cmin” concentration at end of dosing interval as “C”).

Table 1: Drug Interactions

Medicinal products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Antiviral active substances

Tenofovir disoproxil / Dolutegravir1

Tenofovir disoproxil / Rilpivirine1,2

Dolutegravir ↔   AUC ↑ 1%

Cmax ↓ 3%

C ↓ 8%

Tenofovir ↔

Rilpivirine

AUC ↔

Cmin ↔

Cmax ↔

Tenofovir

AUC ↑ 23%

Cmin ↑ 24%

Cmax ↑ 19%

No dose adjustment is required.

Tenofovir alafenamide / Dolutegravir

Tenofovir alafenamide / Rilpivirine1

Dolutegravir ↔

(Not studied)

Rilpivirine ↔

No dose adjustment is required.

Lamivudine/ Dolutegravir

Lamivudine/ Rilpivirine

Dolutegravir ↔

Rilpivirine ↔

(Not studied)

No dose adjustment is required.

Entecavir/ Dolutegravir

Entecavir/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔

(Not studied)

No dose adjustment is required.

Daclatasvir/ Dolutegravir1

Daclatasvir/ Rilpivirine

Dolutegravir ↔   AUC ↑ 33%   Cmax ↑ 29%   C ↑ 45%

Daclatasvir ↔

Rilpivirine ↔

No dose adjustment is required.

Simeprevir/ Dolutegravir

Simeprevir/ Rilpivirine

Dolutegravir ↔

Rilpivirine ↔   AUC ↔   Cmin ↑ 25%   Cmax ↔

Simeprevir ↔   AUC ↔   Cmin ↔   Cmax ↑ 10%

No dose adjustment is required.

Sofosbuvir / Dolutegravir1

Sofosbuvir / Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔   AUC ↔  Cmin ↔   Cmax ↔

Sofosbuvir ↔   AUC ↔  Cmax ↑ 21%

Sofosbuvir metabolite GS-331007 ↔

AUC ↔   Cmax ↔

No dose adjustment is required.

Ledipasvir/Sofosbuvir / Dolutegravir1

Ledipasvir/Sofosbuvir / Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔   AUC ↓ 5%   Cmin ↓ 7%  Cmax ↓ 3%

Ledipasvir ↔   AUC ↑ 2%   Cmin ↑ 2%  Cmax ↑ 1%

Sofosbuvir ↔  AUC ↑ 5%  Cmax ↓ 4%

Sofosbuvir metabolite GS-331007 ↔   AUC ↑ 8%   Cmin ↑ 10%   Cmax ↑ 8%

No dose adjustment is required.

Sofosbuvir/ Velpatasvir/ Dolutegravir1

Sofosbuvir/ Velpatasvir/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔  AUC ↔   Cmin ↔   Cmax ↔

Sofosbuvir ↔   AUC ↔   Cmax ↔

Sofosbuvir metabolite GS-331007 ↔   AUC ↔   Cmin ↔   Cmax ↔

Velpatasvir ↔   AUC ↔   Cmin ↔   Cmax ↔

No dose adjustment is required.

Ribavirin/ Dolutegravir

Ribavirin/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔(Not studied)

No dose adjustment is required.

Other active substances

Antiarrhythmics

Digoxin/ Dolutegravir

Digoxin/ Rilpivirine1

Dolutegravir ↔

(Not studied)

Rilpivirine ↔

Digoxin

AUC ↔

Cmin NA

Cmax ↔

No dose adjustment is required.

Anticonvulsants

Carbamazepine/ Dolutegravir1

Carbamazepine/ Rilpivirine

Dolutegravir ↓  AUC ↓ 49%  Cmax ↓ 33%   C ↓ 73%

Rilpivirine↓

Not studied. Significant decreases in rilpivirine plasma concentrations are expected (induction of CYP3A enzymes).

Metabolic inducers may significantly decrease dolutegravir/rilpivirine plasma concentrations, resulting in loss of therapeutic effect. Co-administration of Juluca with these metabolic inducers is contraindicated (see section 4.3).

OxcarbazepinePhenytoinPhenobarbital/ Dolutegravir

OxcarbazepinePhenytoinPhenobarbital/ Rilpivirine

Dolutegravir ↓

Not studied. Decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected.

Rilpivirine ↓

Not studied. Significant decreases in rilpivirine plasma concentrations are expected

(induction of CYP3A enzymes).

Metabolic inducers may significantly decrease dolutegravir/rilpivirine plasma concentrations, resulting in loss of therapeutic effect. Co-administration of Juluca with these metabolic inducers is contraindicated (see section 4.3).

Azole anti-fungals

Ketoconazole/ Dolutegravir

Ketoconazole/ Rilpivirine1,2

Dolutegravir ↔

(Not studied)

Rilpivirine

AUC ↑ 49%

Cmin ↑ 76%

Cmax ↑ 30%

(inhibition of CYP3A enzymes).

Ketoconazole

AUC ↓ 24%

Cmin ↓ 66%

Cmax ↔

(induction of CYP3A due to high rilpivirine dose in the study).

No dose adjustment is required.

Fluconazole

Itraconazole

Isavuconazole

Posaconazole

Voriconazole/ Dolutegravir

Fluconazole

Itraconazole

Isavuconazole

Posaconazole

Voriconazole/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↑

Not studied. May cause an increase in the plasma concentrations of rilpivirine

(inhibition of CYP3A enzymes).

No dose adjustment is required.

Herbal products

St. John's wort/ Dolutegravir

St. John's wort/ Rilpivirine

Dolutegravir ↓

Not studied. Decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected.

Rilpivirine ↓

Not studied. Significant decreases in rilpivirine plasma concentrations are expected

(induction of CYP3A enzymes).

Co-administration may cause significant decreases in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of Juluca. Co-administration of Juluca with St. John's wort is contraindicated (see section 4.3).

Potassium channel blockers

Fampridine (also known as dalfampridine)/ Dolutegravir

Fampridine ↑

Co-administration of dolutegravir has the potential to cause seizures due to increased fampridine plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Fampridine co-administration with Juluca is contraindicated (see section 4.3).

Proton pump inhibitors

OmeprazoleLansoprazole Rabeprazole PantoprazoleEsomeprazole/ Dolutegravir

Omeprazole/ Rilpivirine1,2

Lansoprazole

Rabeprazole

Pantoprazole

Esomeprazole/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine

AUC ↓ 40%

Cmin ↓ 33%

Cmax ↓ 40%

(reduced absorption due to gastric pH increase).

Omeprazole

AUC ↓ 14%

Cmin NA

Cmax ↓ 14%

Rilpivirine ↓Not studied. Significant decreases in rilpivirine plasma concentrations are expected

(reduced absorption due to gastric pH increase).

Co-administration may significantly decrease rilpivirine plasma concentration. This may result in loss of therapeutic effect of Juluca. Co-administration of Juluca with proton pump inhibitors is contraindicated (see section 4.3).

H2-recepter antagonists

Famotidine Cimetidine Nizatidine Ranitidine/ Dolutegravir

Famotidine/ Rilpivirine1,2

40 mg single dose taken 12 hours before rilpivirine

Famotidine/ Rilpivirine1,2

40 mg single dose taken 2 hours before rilpivirine

Famotidine/ Rilpivirine1,2

40 mg single dose taken 4 hours after rilpivirine

Cimetidine

Nizatidine

Ranitidine/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine

AUC ↓ 9%

Cmin NA

Cmax ↔

Rilpivirine

AUC ↓ 76%

Cmin NA

Cmax ↓ 85%

(reduced absorption due to gastric pH increase).

Rilpivirine

AUC ↑ 13%

Cmin NA

Cmax ↑ 21%

Rilpivirine ↓

Not studied. Significant decreases in rilpivirine plasma concentrations are expected (reduced absorption due to gastric pH increase).

The combination of Juluca and H2-receptor antagonists should be used with particular caution. Only H2-receptor antagonists that can be dosed once daily should be used.

H2-receptor antagonists should be taken well separated in time from the administration of Juluca (minimum 4 hours after or 12 hours before)

Antacids and supplements

Antacids (e.g., aluminium magnesium hydroxide, and/or calcium carbonate)/ Dolutegravir1

Antacids (e.g., aluminium magnesium hydroxide, and/or calcium carbonate)/ Rilpivirine

Dolutegravir ↓   AUC ↓ 74%   Cmax ↓ 72%

C24 ↓ 74%

(Complex binding to polyvalent ions).

Rilpivirine ↓

Not studied. Significant decreases in rilpivirine plasma concentrations are expected

(reduced absorption due to gastric pH increase).

The combination of Juluca and antacids should be used with particular caution. Antacids should be taken well separated in time from the administration of Juluca (minimum 6 hours before or 4 hours after).

Calcium supplements/ Dolutegravir1

Dolutegravir ↓   AUC ↓ 39%   Cmax ↓ 37%   C24 ↓ 39%

(Complex binding to polyvalent ions).

The combination of Juluca and supplements should be used with particular caution. Calcium supplements, iron supplements or multivitamins should be co-administered at the same time as Juluca with a meal.

If calcium supplements, iron supplements or multivitamins cannot be taken at the same time as Juluca, these supplements should be taken well separated in time from the administration of Juluca (minimum 6 hours before or 4 hours after).

Iron supplements/ Dolutegravir1

Dolutegravir ↓   AUC ↓ 54%   Cmax ↓ 57%   C24 ↓ 56%

(Complex binding to polyvalent ions).

Multivitamin/ Dolutegravir1

Dolutegravir ↓

AUC ↓ 33%

Cmax ↓ 35%

C24 ↓ 32%

(Complex binding to polyvalent ions).

Corticosteroids

Prednisone/ Dolutegravir1

Prednisone/ Rilpivirine

Dolutegravir ↔   AUC ↑ 11%

Cmax ↑ 6%

C ↑ 17%

Rilpivirine ↔(Not studied)

No dose adjustment is required.

Dexamethasone/ Dolutegravir

Dexamethasone/ Rilpivirine

(systemic, except for single dose use)

Dolutegravir ↔

(Not studied)

Rilpivirine ↓Not studied. Dose dependent decreases in rilpivirine plasma concentrations are expected

(induction of CYP3A enzymes).

Co-administration may cause significant decreases in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of Juluca. Co-administration of Juluca with systemic dexamethasone is contraindicated (except as a single dose) see section 4.3. Alternatives should be considered, particularly for long-term use.

Antidiabetics

Metformin/ Dolutegravir1

Metformin/ Rilpivirine1

Metformin ↑

AUC ↑ 79%   Cmin NA   Cmax ↑ 66%

Metformin

AUC ↔

Cmin NA

Cmax ↔

A dose adjustment of metformin should be considered when starting and stopping co-administration of Juluca with metformin, to maintain glycaemic control. In patients with moderate renal impairment a dose adjustment of metformin should be considered when co-administered with dolutegravir, because of the increased risk for lactic acidosis in patients with moderate renal impairment due to increased metformin concentration (section 4.4).

Antimycobacterials

Rifampicin/ Dolutegravir1

Rifampicin/ Rilpivirine1,2

Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 43% C ↓72%

(induction of UGT1A1 and CYP3A enzymes).

Rilpivirine

AUC ↓ 80%

Cmin ↓ 89%

Cmax ↓ 69%

(induction of CYP3A enzymes).

Rifampicin

AUC ↔

Cmin NA

Cmax ↔

25-desacetyl-rifampicin   AUC ↓ 9%

Cmin NA

Cmax ↔

Co-administration may cause significant decreases in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of Juluca. Co-administration of Juluca with rifampicin is contraindicated (see section 4.3).

Rifabutin/ Dolutegravir1

Rifabutin/ Rilpivirine1

300 mg once daily2

300 mg once daily

(+ 25 mg once daily rilpivirine)

300 mg once daily

(+ 50 mg once daily rilpivirine)

Dolutegravir ↔   AUC ↓ 5%   Cmax ↑ 16%   C ↓ 30%

(induction of UGT1A1 and CYP3A enzymes).

Rifabutin

AUC ↔

Cmin ↔

Cmax ↔

25-O-desacetyl-rifabutin

AUC ↔

Cmin ↔

Cmax ↔

Rilpivirine

AUC ↓ 42%

Cmin ↓ 48%

Cmax ↓ 31%

Rilpivirine

AUC ↑ 16%*

Cmin ↔*

Cmax ↑ 43%*

* compared to 25 mg once daily rilpivirine alone

(induction of CYP3A enzymes).

Co-administration is likely to cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). When Juluca is co-administered with rifabutin, an additional 25 mg tablet of rilpivirine per day should be taken at the same time with Juluca, for the duration of the rifabutin co-administration (a separate formulation of rilpivirine is available for this dose adjustment, see section 4.2).

Rifapentine/ Dolutegravir

Rifapentine/ Rilpivirine

Dolutegravir ↓

(Not studied)

Rilpivirine ↓Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

Co-administration may cause significant decreases in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of Juluca (induction of CYP3A enzymes). Co-administration of Juluca with rifapentine is contraindicated (see section 4.3).

Antimalarials

Artemether/ Lumefantrine/ Dolutegravir

Artemether/ Lumefantrine/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↓Not studied. Decreased exposure of rilpivirine is expected

(induction of CYP3A enzymes).

The combination of Juluca and artemether/lumefantrine should be used with caution.

Atovaquone/ Proguanil/ Dolutegravir

Atovaquone/ Proguanil/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔(Not studied).

No dose adjustment is required.

Macrolide antibiotics

Clarithromycin

Erythromycin /Dolutegravir

Clarithromycin

Erythromycin /Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↑Not studied. Increased exposure of rilpivirine is expected

(inhibition of CYP3A enzymes).

Where possible, alternatives such as azithromycin should be considered.

Oral contraceptives

Ethinyl estradiol (EE)1 and Norelgestromin (NGMN)1 / Dolutegravir

Ethinyl estradiol (EE)1 and Norethindrone1/ Rilpivirine

Dolutegravir ↔

EE ↔   AUC ↑ 3%   Cmax ↓ 1%

NGMN ↔   AUC ↓ 2%   Cmax ↓ 11%

Rilpivirine ↔*

EE ↔   AUC ↔   Cmin ↔   Cmax ↑ 17%

Norethindrone ↔

AUC ↔   Cmin ↔

Cmax ↔

*based on historic controls.

Dolutegravir or rilpivirine did not change ethinyl estradiol and norelgestromin (dolutegravir) or norethindrone (rilpivirine) plasma concentrations to a clinically relevant extent. No dose adjustment of oral contraceptives is required when co-administered with Juluca.

Analgesics

Methadone/ Dolutegravir1

Methadone / Rilpivirine1

Dolutegravir ↔

Methadone ↔   AUC ↓ 2%   Cmax ↔ 0%   C ↓ 1%

Rilpivirine:

AUC: ↔*

Cmin: ↔*

Cmax: ↔*

R(-) methadone:

AUC: ↓ 16%

Cmin: ↓ 22%

Cmax: ↓ 14%

*based on historic controls.

No dose adjustments are required when initiating co-administration of methadone with Juluca. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Paracetamol/ Dolutegravir

Paracetamol / Rilpivirine1,2

Dolutegravir ↔

(Not studied)

Rilpivirine

AUC ↔

Cmin ↑ 26%

Cmax ↔

Paracetamol

AUC ↔

Cmin NA

Cmax ↔

No dose adjustment is required.

Anticoagulants

Dabigatran etexilate/ Dolutegravir

Dabigatran etexilate/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔

Not studied. Dabigatran etexilate ↑A risk for increases in dabigatran plasma concentrations cannot be excluded

(inhibition of intestinal P-gp).

The combination of Juluca and dabigatran etexilate should be used with caution.

HMG CO-A reductase inhibitors

Atorvastatin/ Dolutegravir

Atorvastatin/ Rilpivirine1,2

Dolutegravir ↔

(Not studied)

Rilpivirine

AUC ↔

Cmin ↔

Cmax ↓ 9%

Atorvastatin

AUC ↔

Cmin ↓ 15%

Cmax ↑ 35%

No dose adjustment is required.

Phosphodiesterase type 5 (PDE-5) inhibitors

Sildenafil / Dolutegravir

Sildenafil/ Rilpivirine1,2

Dolutegravir ↔

Rilpivirine

AUC ↔

Cmin ↔

Cmax ↔

Sildenafil

AUC ↔

Cmin NA

Cmax ↔

No dose adjustment is required.

Vardenafil

Tadalafil/ Dolutegravir

Vardenafil

Tadalafil/ Rilpivirine

Dolutegravir ↔

(Not studied)

Rilpivirine ↔(Not studied)

No dose adjustment is required.

1 The interaction between dolutegravir and/or rilpivirine and the medicinal product was evaluated in a clinical study. All other drug-drug interactions shown are predicted. 2 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing the maximal effect on the co-administered drug.

NA = Not applicable

QT prolonging medicinal products

There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1). Juluca should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes.

4.6. Fertility, pregnancy and lactation

Pregnancy

Lower exposures of dolutegravir and rilpivirine were observed during pregnancy (see sections 5.1, 5.2). In phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure. The use of Juluca during pregnancy is not recommended.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity associated with dolutegravir. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of rilpivirine.

There are no or limited amount (less than 300 exposed outcomes) from the use of this dual combination in pregnancy.

The safety and efficacy of a dual therapy with dolutegravir + rilpivirine has not been studied in pregnancy.

Two large birth outcome surveillance studies (over 14,000 pregnancy outcomes) in Botswana (Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defects after dolutegravir exposure.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%).

Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects (0.11%) in infants whose mothers were taking dolutegravir at conception (over 9,400 exposures) compared to those taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared to women without HIV (0.07%).

Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infants whose mothers were taking dolutegravir at conception (over 4,800 exposures), as infants of women without HIV (0.08%).

Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with first trimester dolutegravir and between 300-1000 pregnancies with first trimester rilpivirine treatment, do not indicate an increased risk of major birth defects with either dolutegravir or rilpivirine compared to the background rate or women with HIV. There are no or limited amount of APR data (less than 300 first trimester exposures) from the use of dolutegravir + rilpivirine in pregnant women.

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified. For rilpivirine, animal studies do not indicate reproductive toxicity (see section 5.3).

Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration.

There is insufficient information on the effects of dolutegravir on neonates.

Breast-feeding

It is unknown if rilpivirine is excreted in human milk. Available toxicological data in animals has shown excretion of rilpivirine in milk. Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). There is insufficent information on the effects of dolutegravir in newborns/infants.

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

Fertility

There are no data on the effects of dolutegravir or rilpivirine on human male or female fertility. Animal studies indicate no clinically relevant effects on male or female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of Juluca. The clinical status of the patient and the adverse reaction profile of Juluca should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8. Undesirable effects

Summary of the safety profile

Clinical safety data with Juluca is limited. The most frequently reported adverse reactions considered possibly or probably related to the combined administration of dolutegravir plus rilpivirine in 513 HIV-1 infected subjects in the Phase III clinical trials (see section 5.1), were diarrhoea (2%) and headache (2%).

The most severe adverse reaction, possibly related to the treatment with dolutegravir (from pooled from Phase IIb and Phase III clinical studies), seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to treatment with the components of Juluca from clinical studies and post-marketing experience are listed in Table 2 by body system, organ class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 2: Tabulated summary of adverse reactions to Juluca based on clinical study and post-marketing experience with Juluca and its individual components

System Organ Class (SOC)

Frequency category1

Adverse drug reactions

Blood and lymphatic systems disorders:

common

decreased white blood cell count decreased haemoglobin decreased platelet count

very rare

sideroblastic anaemia2

Immune system disorders

uncommon

hypersensitivity (see section 4.4)

not known

immune reconstitution syndrome

Metabolism and nutrition disorders

very common

increased total cholesterol (fasted) increased LDL cholesterol (fasted)

common

decreased appetite increased triglycerides (fasted)

Psychiatric disorders

very common

insomnia

common

abnormal dreams depression sleep disorders depressed moodanxiety

uncommon

suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness), panic attack

rare

completed suicide (particularly in patients with a pre-existing history of depression or psychiatric illness)

Nervous system disorders

very common

headache dizziness

common

somnolence

Gastrointestinal disorders

very common

nausea increased pancreatic amylasediarrhoea

common

abdominal pain vomiting flatulenceincreased lipase abdominal discomfort

upper abdominal paindry mouth

Hepatobiliary disorders

very common

increased transaminases

(alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations)

common

increased bilirubin

uncommon

hepatitis

rare

acute hepatic failure3

Skin and subcutaneous tissue disorders

common

rashpruritus

Musculoskeletal and connective tissue disorders

uncommon

arthralgiamyalgia

General disorders and administration site conditions

common

fatigue

Investigations

common

creatine phosphokinase (CPK) elevations, weight increased

1 Frequencies are assigned based on the maximum frequencies observed in the pooled SWORD studies or studies with the individual components

2 Reversible sideroblastic anaemia has been reported in dolutegravir-containing regimens. The contribution of dolutegravir in these cases is unclear.

3 This adverse reaction was identified through post-marketing surveillance for dolutegravir in combination with other ARVs. The frequency category of rare was estimated based on post-marketing reports.

Description of selected adverse reactions

Changes in laboratory biochemistries

Dolutegravir or rilpivirine have been associated with increases in serum creatinine occurring in the first week of treatment when administered with other antiretroviral medicinal products. Increases in serum creatinine occurred within the first four weeks of treatment with Juluca and remained stable through 148 weeks. A mean change from baseline of 9.86 μmol/L (SD 10.4 μmol/L) was observed after 148 weeks treatment. These changes are related to inhibition of active transport, and are not considered to be clinically relevant as they do not reflect a change in glomerular filtration rate.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No specific symptoms or signs have been identified following acute overdose with dolutegravir or rilpivirine apart from those listed as adverse reactions.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of Juluca. If overdose occurs, the patient should be treated supportively with appropriate monitoring, including monitoring of vital signs and ECG (QT interval), as necessary. As dolutegravir and rilpivirine are highly bound to plasma proteins, dialysis is unlikely to result in significant removal of the active substances.